Eltrombopag+hATG+CsA vs. hATG+CsA in Children With Severe AA

Brief description of study

The analysis of our own clinical data suggests that majority of the hematologic responses
observed after the course of h-ATG/CsA is partial, and about 10% tend to have cyclosporine
dependence.

The aim of the current study is to improve the rate and the quality of hematologic response
as well as to prevent delayed complications such as relapse and clonal progression by means
of adding eltrombopag to standard immunosuppressive therapy

Detailed Study Description

This trial will evaluate safety and efficacy of combination eltrombopag with standard
hATG/CSA as first line therapy in patients with SAA. The primary endpoint is going to be
estimating the rate of complete hematologic response at the point in four months after the
end of the treatment. Secondary endpoints are probability of relapse, hematologic blood count
recovery in 6 and 12 months after the treatment, survival, clonal evolution into
myelodysplasia and leukemia

Aplastic anemia can be treated effectively with allogeneic bone marrow transplantation and
immunosuppressive therapy with horse anti-thymocyte globulin (h-ATG) and cyclosporine (CsA),
allowing to achieve a comparable long-term survival about 80%. However, one third of the
patients treated with h-ATG/CsA, does not respond, and 25-30% of the responders relapse. The
analysis of our clinical data suggests that majority of the hematologic responses observed
following initial h-ATG/CsA are partial, with only a few patients achieving normal blood
counts, and about 10% tend to have cyclosporine dependence. Although horse ATG/CsA provides
represented a major advance in the treatment of SAA, such condition as refractory course of
the disease, incomplete response, relapse, and clonal evolution limit the success of this
treatment. Thus, new regimens are needed to overcome these limitations and provide a better
alternative to stem cell transplantation.

One option of improving the quality of hematologic responses is influencing underlying stem
cell function. Previous attempts to improve response by hematopoietic cytokines, including
erythropoietin and G-CSF, have failed. Thrombopoietin is the principal endogenous regulator
of platelet production. In addition, TPO also has stimulatory effects onto primitive
multilineage progenitors and stem cells in vitro and animal models. Eltrombopag (Revolade),
an oral 2nd generation small molecule TPO-agonist, is approved for treatment of chronic
immune thrombocytopenic purpura and SAA who had insufficient response to immunosuppressive
therapy. Eltrombopag increases platelets in healthy subjects and in thrombocytopenic
patients, and recently has showed clinically significant hematologic responses in refractory
SAA patients. The aim of this tudy to improve hematologic response rate and its quality, as
well as to prevent late complications such as relapse and clonal progression, by adding
eltrombopag into standard immunosuppressive therapy This trial evaluates safety and efficacy
of combining eltrombopag with standard hATG/CSA as the first line of therapy in patients with
SAA. The primary endpoint is going to be estimation of the rate of complete hematologic
response in 4 months. Secondary endpoints are probability of relapse, robust hematologic
blood count recovery in 6 and 12 months after the treatment, survival, clonal evolution to
myelodysplasia and leukemia.

This is a trial aiming to increase 4 months overall response rate. The sample size is
calculated on the hypothesis that the experimental treatment will increase the 4 months
response rate in 20% in comparison with standard IST treatment arm. Under these assumptions,
the sample size to reject the null hypothesis is n=100 patients, 50 patients in each
treatment arm; alpha-error 0.05; power 0.75.